1. Field of the Invention
The present invention relates to anticonvulsant drugs, and processes for using such drugs, wherein the drugs are based on 3- and 4-amino-N(alkyl phenyl) benzamide compounds. The most preferred of such benzamide compounds for this utility is 4-amino-N-(2,6-dimethyl phenyl)-benzamide.
2. Description of the Prior Art
The several anticonvulsant drugs marketed to date in the United States provide significant seizure relief for only 50-75% of epileptic patients. The therapeutic effects are sometimes accompanied by serious side effects such as sedation, ataxia, psychoses, suicidal depression, gastrointestinal disturbances, gingival hyperplasia, lymphadenopathies, megaloblastic anemias, hepatotoxicity, nephropathies, hirsutism, and fetal malformations. These side effects, which range in severity from mild sedation to death from aplastic anemia, are particularly troublesome since most of the marketed anticonvulsants have very low therapeutic ratios. For example, phenytoin, one of the most widely used anticonvulsants, controls seizures in man only when plasma levels reach 10 mcg/ml. Toxic effects such as nystagmus are seen at around 20 mcg/ml, ataxia is obvious at 30 mcg/ml, and lethargy is apparent at about 40 mcg/ml. See in this regard "The Pharmacological Basis of Therapeutics" (Gilman, Goodman, and Gilman, ed., 6th Ed., MacMillan Publishing Co., Inc., New York, New York, (1980)), p. 455. In view of these facts, most epileptologists indicate there is a definite need for more selective and less toxic anticonvulsant drugs.
U.S. Pat. No. 4,379,165 which issued Apr. 5, 1983 and J. Medicinal Chemistry, 1984, Vol. 27, pages 779 to 782 disclose the use as anti-convulsants of certain amino-benzamide compounds. Although these compounds have a useful level of anticonvulsant activity when compared to previously employed prototype antiepileptic drugs such as phenobarbitol, phenytoin, mephenytoin and carbamazepine, such levels of anticonvulsant activity require the use of relatively large doses of such materials to impart the desired level of such activity and thus increase the danger of causing undesired toxic side effects. The amino-benzamide compounds of these two publications are also of limited scope, structurally. For example, none of the phenyl or benzyl groups contain any ring substituents other than the amino group in the benzamide radical.
The compounds 4-amino-N-(2-methyl phenyl) benzamide, 4-amino-N-(4-methyl phenyl) benzamide and 4-amino-N-(2,6-dimethyl phenyl) benzamide, among others, and a process for their preparation, are disclosed by P. Grammaticakis in Compt. Rend., 259, (23), Page 4295 1965 and also in Chemical Abstracts 62:11732b(1965). No utility is disclosed for these compounds in these publications.
Chem. Abs., Vol. 75; 1971; 35466g and Chem. Abs, Vol. 76, 1972, 140260d disclose the preparation, and use as analgesics, antiinflammatory, antipyretic or antiphlosgistics, of certain selected 4-amino benzoic acid anilides.
Prior to the present invention it has not been possible to provide anticonvulsant drugs which would provide levels of anticonvulsant activity significantly better then the levels provided by phenytoin and carbamazepine which provide levels of antimaximal electroshock (MES) activity in mice of the order of about 8.81 to 9.50 MES ED.sub.50 (mg/kg) when employing an intraperitoneal dosage, and as otherwise described herein, or in the Appendix hereto.
The amino-benzamide compounds of U.S. Pat. No. 4,379,165 and of the J. Medicinal Chemistry publication, supra, provide activity levels in mice of the order of about 18 to 67 MES ED.sub.50 (mg/kg) under the same test conditions.
An object of the present invention, therefore, is to provide, as a novel class of anticonvulsant drugs certain 3- and 4-amino (alkyl phenyl) benzamides, some of which have significantly improved levels of anticonvulsant activity as compared to the previously available anticonvulsant drugs.
A further object of the present invention is to provide anti-convulsant drugs which are relatively safe to use at dosage levels providing useful levels of anticonvulsant activity.
Another object of the present invention is to provide anticonvulsant drugs that may be effectively administered orally.
Another object of the present invention is to provide certain novel 3- and 4-amino (alkyl phenyl) benzamides which may be used as anticonvulsant drugs.